Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease
自身免疫性肺病新模型的机制和抗原鉴定
基本信息
- 批准号:8504518
- 负责人:
- 金额:$ 12.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdoptive TransferAllelesAnimal ModelAnimalsAntibodiesAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesBiological AssayBiological MarkersBlood TestsBronchiolitisBronchiolitis Obliterans Organizing PneumoniaCaliforniaCell Cycle KineticsCellsClinicalComplicationCritical CareDataDefectDevelopmentDevelopment PlansDiagnosisDiseaseDoseEnvironmentExperimental ModelsFailureFibrosisFoundationsFutureGenesGoalsGrantHomologous GeneHumanHuman CloningImmuneImmune ToleranceImmune responseImmunoblottingImmunohistochemistryImmunologyImmunosuppressionInjuryInterstitial Lung DiseasesInterstitial PneumoniaKnockout MiceLaboratoriesLeadLearningLifeLungLung TransplantationLung diseasesLymphoid interstitial pneumoniaMediatingMentorsModelingMouse ProteinMusMutationOrganPathogenesisPatientsPatternPeptide/MHC ComplexPhenotypePhysiciansPopulationPrincipal InvestigatorProteinsPulmonary FibrosisRadioimmunoassayRegulator GenesResearchResearch PersonnelRheumatoid ArthritisRiskRoleSan FranciscoScientistSclerodermaSerumSeveritiesStructure of parenchyma of lungSyndromeT-LymphocyteTestingTherapeuticThymus GlandTrainingTraining ProgramsTransgenic OrganismsTranslatingTranslational ResearchUniversitiesVariantVascular DiseasesWorkagedauthorityautoreactive T cellbasecareercareer developmentcell typecohortcytokinedesigndisease mechanisms studyeffective therapyexperiencefundamental researchgene cloningimmunopathologyimmunoreactivityinjuredinterstitiallung developmentlung injurymouse modelnoveloutcome forecastprofessorresearch studyresponseskillssystemic autoimmune diseasetherapy designthymocytetool
项目摘要
Pulmonary disease is a frequent complication of systemic autoimmune diseases, often requiring
aggressive treatment with high dose immunosuppression or lung transplantation. Despite the significant
clinical impact, little is understood about the pathogenesis of lung disease in autoimmune conditions. As a
pulmonary and critical care physician at the University of California, San Francisco, Dr. Anthony Shum is
establishing himself as an investigator in the mechanisms of autoimmune-mediated lung disease. With the
highly regarded Immunology Training Program and an internationally recognized mentoring team, UCSF
provides the ideal environment for the critical studies and intensive training necessary for Dr. Shum's
development towards his long-term goal of a career as a physician-scientist. The primary mentor, Dr. Mark
Anderson, is a leading expert in central immune tolerance, and co-mentor, Dr. Harold Chapman, Professor
and Chief of the Pulmonary Division, is a renowned authority on lung injury and tissue remodeling.
A major barrier to research on lung autoimmunity has been the lack of animal models in which to study
disease pathogenesis. Using the Aire (Autoimmune Regulator) deficient mouse, Dr. Shum's research
presents the unique opportunity to define basic mechanisms of autoimmune lung disease in a novel model
of a known human autoimmune syndrome. Autoimmune Polyglandular Syndrome 1 (APS1) arises from
mutations in the AIRE gene and like their human counterparts, Aire deficient mice develop autoimmunity to
multiple organs, including the lung, due to a critical breakdown in central immune tolerance. Importantly,
Aire deficient mice develop interstitial lung disease spontaneously in a pattern strikingly similar to APS1
patients. Furthermore, Dr. Shum has identified a novel lung autoantigen in the Aire deficient mouse that may
be the key to initiating disease. Thus, we hypothesize that pulmonary disease in Aire KO mice is due to a
failure to tolerize thymocytes to a critical lung antigen, resulting in the escape of autoreactive T cells that
target and injure the lung. To address this hypothesis, the proposed specific aims are to: (1) determine the
cell populations that mediate lung disease in Aire KO mice; (2) establish the role of our lung antigen in the
pathogenesis of pulmonary disease in the mouse model; and (3) establish the role of the human homolog of
RELEVANCE (Seeinstructions). In this project we will learn how lung damage occurs in systemic autoimmune
diseases like rheumatoid arthritis or scleroderma. We will identify the cells that are attacking the lung, which
lung proteins they are targeting, and how they cause injury. In doing so, we will be able to develop blood
tests to help physicians diagnose patients with autoimmune lung disease and determine their prognosis. We
also seek to design therapies made specifically for the lung to effectively treat patients with these disorders.
肺部疾病是全身性自身免疫性疾病的常见并发症,通常需要
采用大剂量免疫抑制或肺移植的积极治疗。尽管重要的是
临床影响方面,对自身免疫条件下肺部疾病的发病机制知之甚少。作为一名
加州大学旧金山分校的肺部和重症监护内科医生Anthony Shum博士
在自身免疫介导的肺部疾病的机制方面确立了自己的研究者地位。与
备受推崇的免疫学培训计划和国际公认的指导团队--加州大学旧金山分校
为沈博士的批判性研究和强化培训提供了理想的环境
朝着他作为内科科学家的职业生涯的长期目标发展。主要导师马克博士
安德森是中枢免疫耐受方面的领先专家,也是哈罗德·查普曼教授的共同导师。
肺科主任,是肺损伤和组织重建方面的知名权威。
肺自身免疫研究的一个主要障碍是缺乏可供研究的动物模型
疾病发病机制。使用Aire(自身免疫调节因子)缺陷的小鼠,沈博士的研究
提供了在新模型中确定自身免疫性肺病基本机制的独特机会
一种已知的人类自身免疫综合症。自身免疫性多腺体综合征1(APS1)是由
Aire基因的突变和它们的人类同行一样,Aire缺陷的小鼠产生了自身免疫力,以
多个器官,包括肺,由于中枢免疫耐受严重崩溃。重要的是
AIRE缺陷小鼠自发发生间质性肺疾病,其模式与APS1惊人地相似
病人。此外,沈博士还在Aire缺陷小鼠身上发现了一种新的肺自身抗原,它可能
是引发疾病的关键。因此,我们假设Aire KO小鼠的肺部疾病是由于
胸腺细胞不能耐受一种关键的肺抗原,导致自身反应性T细胞逃逸
瞄准并损伤肺部。为了解决这一假设,提出的具体目标是:(1)确定
介导Aire KO小鼠肺部疾病的细胞群;(2)确定我们的肺抗原在
在小鼠模型中肺部疾病的发病机制;以及(3)确定人类同源基因在
相关性(参见说明)。在这个项目中,我们将学习肺损伤是如何在全身自身免疫中发生的。
类风湿性关节炎或硬皮病等疾病。我们将确定攻击肺部的细胞,这些细胞
他们的目标肺蛋白,以及它们是如何造成损伤的。在这样做的时候,我们将能够发展血液
帮助医生诊断自身免疫性肺部疾病患者并确定其预后的测试。我们
还寻求设计专门针对肺部的疗法,以有效地治疗这些疾病的患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Anthony Shum其他文献
Anthony Shum的其他文献
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{{ truncateString('Anthony Shum', 18)}}的其他基金
Unraveling the molecular mechanisms of impaired central tolerance in COPA syndrome
揭示 COPA 综合征中枢耐受受损的分子机制
- 批准号:
10581676 - 财政年份:2022
- 资助金额:
$ 12.18万 - 项目类别:
Defining the molecular mechanisms of COPA syndrome through computational modeling and functional studies
通过计算模型和功能研究定义 COPA 综合征的分子机制
- 批准号:
10388222 - 财政年份:2021
- 资助金额:
$ 12.18万 - 项目类别:
Defining the molecular mechanisms of COPA syndrome through computational modeling and functional studies
通过计算模型和功能研究定义 COPA 综合征的分子机制
- 批准号:
10196529 - 财政年份:2021
- 资助金额:
$ 12.18万 - 项目类别:
Defining the Role of Thymic Tolerance in the Pathogenesis of the COPA syndrome
定义胸腺耐受性在 COPA 综合征发病机制中的作用
- 批准号:
10083697 - 财政年份:2018
- 资助金额:
$ 12.18万 - 项目类别:
Defining the Role of Thymic Tolerance in the Pathogenesis of the COPA syndrome
定义胸腺耐受性在 COPA 综合征发病机制中的作用
- 批准号:
10319566 - 财政年份:2018
- 资助金额:
$ 12.18万 - 项目类别:
Translational studies of autoimmune-mediated lung disease
自身免疫介导的肺部疾病的转化研究
- 批准号:
8818509 - 财政年份:2014
- 资助金额:
$ 12.18万 - 项目类别:
Translational studies of autoimmune-mediated lung disease
自身免疫介导的肺部疾病的转化研究
- 批准号:
8966038 - 财政年份:2014
- 资助金额:
$ 12.18万 - 项目类别:
Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease
自身免疫性肺病新模型的机制和抗原鉴定
- 批准号:
7883278 - 财政年份:2009
- 资助金额:
$ 12.18万 - 项目类别:
Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease
自身免疫性肺病新模型的机制和抗原鉴定
- 批准号:
8098804 - 财政年份:2009
- 资助金额:
$ 12.18万 - 项目类别:
Mechanisms and Antigen Identification in a Novel Model of Autoimmune Lung Disease
自身免疫性肺病新模型的机制和抗原鉴定
- 批准号:
8286951 - 财政年份:2009
- 资助金额:
$ 12.18万 - 项目类别:
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